Year: 2013
Type: review
Abstract: The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction.
Source: Neurobiology of Disease
Authors: Hilary Highfield Nickols, P. Jeffrey Conn
Institution: Vanderbilt University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,180
Awards: Muscarinic Receptor Activators as Antipsychotic Agents, Development of mGIuR5 NAMS for Treatment of Major Depression, Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia, Functions of Metabotropic Glutamate Receptor Subtypes, Regulation of Signaling by mGluR5, Functions of Metabotropic Glutamate Receptor Subtypes
OpenAlex ID: W2009664257